This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Bladder cancer is the 4th most prevalent cancer in men and the 11th in women. Despite its impact on human health, therapeutic approaches against this malignancy are limited. Under normal conditions, bladder epithelial cells assemble as a tightly sealed, non-permeable barrier bearing a thick layer of glycosaminoglycans (GAG) that greatly contributes to isolate the urothelium from the urine. However, upon carcinoma development, relatively undifferentiated tumor cells, less competent for secretion, become exposed while normal cells remain shielded by the GAG layer. Those uncovered tumor cells are suitable targets for cytotoxic agents. However, dilution of the bladder content by constant urine influx and periodical voiding constitute major challenges for therapeutic approaches with poor or non-existing cell binding/targeting.
Current adjuvant therapies for bladder cancer use live Bacillus Calmette-Guerin (BCG) to target bladder tumor cells and trigger an anti-tumor immune response. The ability of BCG to bind the exposed tumor cells via its fibronectin attachment protein (FAP) allows the bacterium to overcome the above mentioned problems (dilution by urine influx and elimination by bladder content voiding). However, this is not a primary anti-cancer therapy and quickly leads to patient hypersensitivity (usually producing abandonment of the treatment), morbidity and risk of infection. Purified proteins such as FAP and other ligands may provide targeting substitutes devoid of these undesirable secondary effects; however, as opposed to BCG, they are not multivalent and several of molecules are required to be tied together to induce a rate of uptake by tumor cells meaningful for patient treatment. See Coon, et al. (Int. J. Cancer, 2012, 131(3):591-600).